Method for producing enantiomer-free 6,8 dihydroxy octanoic acid esters by means of asymmetric, catalytic hydrogenation

ABSTRACT

The invention relates to a process for the preparation of compounds of the general formula I 
                 
 
in which R 1  represents a C 1 -C 20 -alkyl group, a C 3 -C 12 -cycloalkyl group, a C 7 -C 12 -aralkyl group or a mono- or bi-nuclear aryl group, in which a ketone of formula II 
                 
 
wherein R 1  is as defined above, is subjected to asymmetric hydrogenation.

TECHNICAL FIELD

The present invention relates to a novel process for the preparation ofenantiomerically pure 6,8-dihydroxyoctanoic acid esters of the generalformula I, wherein R¹ represents a C₁-C₂₀-alkyl group, aC₃-C₁₂-cycloalkyl group, a C₇-C₁₂-aralkyl group or a mono- or bi-nucleararyl group.

The invention relates also to novel compounds of formulae II and III,which are used as starting compounds or intermediates in the synthesisof the compounds (R)-I and (S)-I.

PRIOR ART

The compounds (R)-I and (S)-I are known. They are both usedpredominantly as intermediates for the synthesis of enantiomericallypure α-lipoic acid of formula IV and its derivatives. α-Lipoic acid is1,2-dithiolane-3-pentanoic acid (thioctic acid).

The (R)-enantiomer of α-lipoic acid (R)-(+)-IV is a natural substancewhich occurs in small concentrations in virtually all animal andvegetable cells. α-Lipoic acid is of crucial importance as a coenzyme inthe oxidative decarboxylation of α-ketocarboxylic acids (e.g. pyruvicacid). α-Lipoic acid is pharmacologically active and has antiphlogisticand antinociceptive (analgesic) properties, as well as cytoprotectiveproperties. An important medicinal indication of racemic α-lipoic acidis the treatment of diabetic polyneuropathy. According to more recentresults (A. Baur et al., Klin. Wochenschr. 1991, 69, 722; J. P. Merin etal., FEBS Lett. 1996, 394, 9) α-lipoic acid may possibly gain importancein the control of diseases caused by HIV-1 and HTLV IIIB viruses.

In the case of the pure optical isomers of α-lipoic acid (R- and S-form,i.e (R)-α-lipoic acid and (S)-α-lipoic acid), in contrast to theracemate, the (R)-enantiomer, has predominantly antiphlogistic activityand the (S)-enantiomer has predominantly antinociceptive activity (EP0427247, 08.11.90). The two enantiomers have also been found to havedifferent pharmacokinetic properties (R. Hermann et al., Eur. J.Pharmaceut. Sci. 1996, 4, 167; G. Raddatz and H. Bisswanger, J.Biotechnol. 1997, 58, 89; T. M. Hagen et al., FASEB J. 1999, 13, 411).The synthesis of the pure enantiomers is therefore of great importance.

Known processes for preparing enantiomerically pure (α-lipoic acidsinclude racemate cleavage of α-lipoic acid or its precursors, asymmetricsyntheses using chiral auxiliaries, chiral pool syntheses usingnaturally occurring optically active starting compounds, and alsomicrobial syntheses (overview article: J. S. Yadav et al., J. Sci. Ind.Res. 1990, 49, 400; and also: E. Walton et al., J. Am. Chem. Soc. 1955,77, 5144; D. S. Acker and W. J. Wayne, J. Am. Chem. Soc. 1957, 79, 6483;L. G. Chebotareva and A. M. Yurkevich, Khim.-Farm. Zh. 1980, 14, 92; A.S. Gopalan et al., Tetrahedron Lett. 1989, 5705; A. G. Tolstikov et al.,Bioorg. Khim. 1990, 16, 1670; L. Dasaradhi et al., J. Chem. Soc., Chem.Commun. 1990, 729; A. S. Gopalan et al., J. Chem. Perkin Trans. 1 1990,1897; EP 0487986 A2, 14.11.91; R. Bloch et al., Tetrahedron 1992, 48,453; B. Adger et al., J. Chem. Soc., Chem. Commun. 1995, 1563; DE-OS19533881.1, 13.09.95; DE-OS 19533882.1, 13.09.95; Y. R. Santosh Laxmiand D. S. Iyengar, Synthesis, 1996, 594; M. Bezbarua et al., 1996, 1289;N. W. Fadnavis et al., Tetrahedron: Asymmetry 1997, 8, 337; N. W.Fadnavis et al., Tetrahedron: Asymmetry 1998, 9, 4109; S. Lee and Y.Ahn, J. Korean Chem. Soc. 1999, 43, 128).

Of those processes, racemate cleavage via the formation ofdiastereoisomeric salts of α-lipoic acid with optically activeα-methylbenzylamine (DE-OS 4137773.7, 16.11.91 and DE-OS 4427079.8,30.07.94) represents the most economical variant hitherto. However,because the racemate separation does not take place until the last stageof the synthesis sequence, high yields cannot be achieved.

The known chemocatalytic asymmetric processes for the preparation ofenantiomerically pure α-lipoic acid (DE-OS 3629116.1, 27.08.86; DE-OS19709069.1, 6.03.97); R. Zimmer et al., Tetrahedron: Asymmetry 2000, 11,879) are uneconomical because of the high costs of the startingcompounds.

The object of the invention is, therefore, to make available, asdesired, the 6,8-dihydroxyoctanoic acid esters (R)-I and (S)-I leadingto the two enantiomers of α-lipoic acid, in a high chemical and opticalspace-time yield using inexpensive starting materials.

DESCRIPTION OF THE INVENTION

According to the invention, that is achieved by asymmetricchemocatalytic hydrogenation of 8-hydroxy-6-oxo-octanoic acid esters offormula II, in which R¹ represents a C₁-C₂₀-alkyl group, aC₃-C₁₂-cycloalkyl group, a C₇-C₁₂-aralkyl group or a mono- or bi-nucleararyl group, in the presence of complexes consisting of ruthenium andoptically active phosphines.

The compounds II are novel and can be obtained by selectivehydrogenation of the 7,8-epoxy-6-oxo-octanoic acid esters III,preferably in the presence of platinum, palladium or nickel catalysts.

The preparation of the 7,8-epoxy-6-oxo-octanoic acid esters III, whichare also novel, is possible in high yields by epoxidation of6-oxo-7-octenoic acid esters of formula V, preferably by means of sodiumpercarbonate in methanol. The compounds V are known and are obtainableby elimination of hydrogen chloride from 8-chloro-6-oxo-octanoic acidesters, which are used as inexpensive starting compounds for thecommercial synthesis of racemic α-lipoic acid (M. W. Bullock et al., J.Am. Chem. Soc. 1954, 76, 1828).

Alternatively, racemic 6,8-dihydroxyoctanoic acid esters of formula Ican be converted into compounds of formula II by regioselectiveoxidation of the secondary hydroxy group, preferably by means of sodiumhypochlorite in acetic acid. The preparation of racemic6,8-dihydroxyoctanoic acid esters of formula I is known and can becarried out, inter alia, starting from butadiene and acetic acid (J.Tsuji et al., J. Org. Chem. 1978, 43, 3606).

Ruthenium-diphosphine complexes are of particular interest as catalystsfor the asymmetric hydrogenation of the compounds II. As typical butnon-limiting examples there may be mentioned the ruthenium complexes ofthe following formulae VI to XII:

[RuHa1₂D]_(n)(L)_(x) VI [RuHa1AD]⁺Y⁻ VII RuD_(n)OOCR²OOCR³ VIII[RuH_(x)D_(n)]^(m+)Y_(m) ⁻ IX [RuHa1 (PR⁴ ₂R⁵)D]²⁺Hal₂ ⁻ X [RuHHalD₂] XI[DRu (acac)₂] XIIwherein:

-   -   acac represents acetyl acetonate,    -   D represents a diphosphine of the general formula XIII,    -   Hal represents halogen, especially iodine, chlorine or bromine,    -   R² and R³ are the same or different and represent alkyl having        up to 9 carbon atoms, preferably up to 4 carbon atoms, which is        optionally substituted by halogen, especially fluorine, chlorine        or bromine, or represent phenyl which is optionally substituted        by alkyl having from 1 to 4 carbon atoms, or represent an        α-aminoalkyl acid having preferably up to 4 carbon atoms, or        together form an alkylidene group having up to 4 carbon atoms,    -   R⁴ and R⁵ are the same or different and represent optionally        substituted phenyl, preferably substituted by alkyl having from        1 to 4 carbon atoms or by halogen,    -   Y represents Cl, Br, I, ClO₄, BF₄ or PF₆,    -   A represents an unsubstituted or substituted benzene ring, such        as p-cymene,    -   L represents a neutral ligand such as acetone, a tertiary amine        or dimethylformamide,    -   n and m each represent 1 or 2,    -   x represents 0 or 1,        wherein in formula IX n represents 1 and m represents 2 when        x=0, and n represents 2 and m represents 1 when x=1.

The complexes of formulae VI to XII can be prepared by methods known perse (VI and XI: EP 174057 and J. P. Genet et al., Tetrahedron Asymmetry1994, 5, 675; VII: EP 366390; VII: EP 245959 and EP 272787; IX: EP256634; X: EP 470756; XII: P. Stahly et al., Organometallics 1993,1467).

As optically active diphosphine ligands there are used compounds of thegeneral formula XIII:

wherein:

-   -   Q represents a group bridging the two P atoms and having from 2        to 24 carbon atoms and optionally from 1 to 4 hetero atoms,        preferably O, S, N and Si, the bridging being formed by at least        2 of the carbon atoms and optionally from 1 to 4 of the hetero        atoms,    -   R⁶-R⁹ are the same or different and represent alkyl groups        having from 1 to 18 carbon atoms, cycloalkyl groups having from        5 to 7 carbon atoms or aryl groups having from 6 to 12 carbon        atoms.

The following ligands may be mentioned as examples of particularlypreferred chiral diphosphines used in enantiomerically pure form:

BINAP: R¹ = Phenyl Tolyl-BINAP: R¹ p-Tolyl

BIMOP: R¹ = Ph, R² = R⁴ = Me, R³ = OMe FUPMOP: R¹ = Ph, R² = R⁴ = CF₃,R³ = OMe BIFUP: R¹ = Ph, R² = R⁴ CF₃, R³ = H BIPHEMP: R¹ = Ph, R² = R³ =H, R⁴ = Me MeO-BIPHEP: R¹ = Ph, R² = R³ = H, R⁴ = OMe BICHEP: R¹ =c-C₆H₁₁, R² = R³ = H, R⁴ = Me

Me-DuPHOS: R¹ = Me Et-DuPHOS: R¹ = Et

BIBFUP

Me-BPE: R¹ = Me iPr-BPE: R¹ = iPr

XIV

CHIRAPHOS

The ligands listed above as racemic structures for the sake ofsimplicity are compounds that are known in their enantiomerically pureforms (BINAP: R. Noyori et al., J. Am. Chem. Soc. 1980, 102, 7932;BIMOP, FUPMOP, BIFUP: M. Murata et al., Synlett 1991, 827; BIBHEMP: R.Schmid et al., Helv. Chim. Acta 1988, 71, 697; MeO-BIPHEP: R. Schmid etal., Helv. Chim. Acta 1991, 74, 370; BICHEP: A. Miyashita et al., Chem.Lett. 1989, 1849; DuPHOS: M. Burk et al., Organometallics 1990, 9, 2653;BPE: M. Burk et al., J. Am. Chem. Soc. 1995, 117, 4423; BIBFUP: EP643065; CHIRAPHOS: B. Bosnich et al., J. Am. Chem. Soc. 1977, 99, 6262;XIV: WO 96/01831).

The asymmetric hydrogenation of the compounds of formula II in thepresence of the above-described optically active ruthenium-diphosphinecomplexes of formulae VI to XII can be carried out in suitable organicsolvents that are inert under the reaction conditions. Special mentionmay be made as such solvents of alcohols, such as methanol or ethanol,chlorinated hydrocarbons, such as methylene chloride or dichloroethane,cyclic ethers, such as tetrahydrofuran or dioxane, esters, such as, forexample, ethyl acetate, aromatic hydrocarbons, such as benzene ortoluene, or also mixtures thereof and the like. In order to suppresspossible ketal formation when working in alcohols as solvent, up to 10vol. % water can be added. The substrate concentrations are preferablyfrom 5 to 50 vol. %, especially from 20 to 40 vol. %.

The reactions can preferably be carried out at temperatures ofapproximately from 10° C. to 140° C., especially approximately from 20°C. to 70° C., and under a hydrogen pressure of approximately from 1 to100 bar, especially from 4 to 50 bar. The reaction times are generallyfrom 2 to 48 hours, mostly from 6 to 24 hours. The molar ratio betweenruthenium in the complexes VI to XII and the compounds II to behydrogenated is advantageously from approximately 0.001 to approximately5 mol %, preferably from approximately 0.005 to approximately 0.2 mol %.

In the reaction, the desired enantiomer of formula I can be obtained bychoosing the optically active diphosphine ligand of formula XIII havingthe appropriate configuration. Accordingly, the use of (R)-(+)-BINAP,for example, yields products of formula (R)-I, and the use of(S)-(−)-BINAP yields products of formula (S)-I.

The compounds (S)-I and (R)-I are used to prepare the enantiomericallypure α-lipoic acids of formula IV by, in known manner (J. D. Gopalan etal., Tetrahedron Lett. 1985, 2535):

-   -   a) converting those compounds, in organic solution, with a        sulfonic acid chloride and a tertiary nitrogen base, into the        bissulfonic acid ester of I,    -   b) reacting that compound, in a polar solvent, with sulfur and        an alkali metal sulfide to form the α-lipoic acid ester, and    -   c) if desired, converting that ester into the respective pure        enantiomer of α-lipoic acid. In that process, the compounds        (R)-I yield (S)-(−)-α-lipoic acid and the compounds (S)-I yield        (R)-(+)-α-lipoic acid.

The compounds (R)-I and (S)-I and (R)-(+)-IV and (S)-(−)-IV prepared bythe process according to the invention generally have a highenantiomeric excess, corresponding to an optical yield of from 90 to99%.

The enantiomeric ratios are measured directly by chiral HPLC or GC onoptically active columns.

By means of the present invention it is possible to make available, inan economical manner and in high chemical and optical yields, theenantiomerically pure 6,8-dihydroxy-octanoic acid esters of the generalformula I (R¹=C₁-C₂₀-alkyl, C₃-C₁₂-cycloalkyl, C₇-C₁₂-aralkyl or mono-or bi-nuclear aryl) as intermediates for the preparation of theenantiomerically pure α-lipoic acids of formula IV.

The Examples which follow illustrate but do not limit the invention.

EXAMPLE 1

43.5 mg (0.087 mmol) of [RuCl₂(C₆H₆)]₂, 113.7 mg (0.183 mmol) of(R)-BINAP and 3 ml of dimethylformamide were placed into a 20 ml Schlenkflask under Argon. The reddish-brown suspension was heated for 10minutes at 100° C. The solution, which was then clear, was cooled andconcentrated in vacuo (1 to 0.1 mmHg) at 50° C. with vigorous stirringover a period of 1 hour. The orange-brown solid that remained was takenup in 1 ml of tetrahydrofuran and was used in that form as aRu-(R)-BINAP catalyst in the asymmetric hydrogenations.

EXAMPLE 2

43.5 mg (0.087 mmol) of [RuCl₂(C₆H₆)]₂, 113.7 mg (0.183 mmol) of(S)-BINAP and 3 ml of dimethylformamide were placed into a 20 ml Schlenkflask under Argon. The reddish-brown suspension was heated for 10minutes at 100° C. The solution, which was then clear, was cooled andconcentrated in vacuo (1 to 0.1 mmHg) at 50° C. with vigorous stirringover a period of 1 hour. The orange-brown solid that remained was takenup in 1 ml of tetrahydrofuran and was used in that form as aRu-(S)-BINAP catalyst in the asymmetric hydrogenations.

EXAMPLE 3

A 100 ml autoclave was charged under argon with 3.8 g (20 mmol) of8-hydroxy-6-oxo-octanoic acid methyl ester, with the Ru-(R)-BINAPcatalyst solution prepared under Example 1, and with 20 ml ofoxygen-free methanol. The hydrogenation was carried out for 20 hours at60° C., at a constant pressure of 40 bar pure H₂ and with intensivestirring. When the reaction was complete, the solvent was distilled offusing a rotary evaporator. Purification of the residue by columnchromatography (silica gel, ethyl acetate/n-hexane) yielded 3.2 g (85%)of (R)-6,8-dihydroxyoctanoic acid methyl ester having an enantiomericexcess of 96% (chiral GC).

EXAMPLE 4

A 100 ml autoclave was charged under argon with 3.8 g (20 mmol) of8-hydroxy-6-oxo-octanoic acid methyl ester, with the Ru-(S)-BINAPcatalyst solution prepared under Example 2, and with 20 ml ofoxygen-free methanol. The hydrogenation was carried out for 20 hours at60° C., at a constant pressure of 40 bar pure H₂ and with intensivestirring. When the reaction was complete, the solvent was distilled offusing a rotary evaporator. Purification of the residue by columnchromatography (silica gel, ethyl acetate/n-hexane) yielded 3.1 g (82%)of (S)-6,8-dihydroxyoctanoic acid methyl ester having an enantiomericexcess of 96% (chiral GC).

EXAMPLE 5

100 ml of aqueous sodium hypochlorite solution (10-13% active chlorine)were added dropwise at room temperature, over a period of 45 minutes, to16.6 g (87 mmol) of 6,8-dihydroxyoctanoic acid methyl ester in 200 ml ofglacial acetic acid. After stirring for a further 3 hours at roomtemperature, 180 ml of isopropanol were added in order to destroy excesssodium hypochlorite, and stirring was carried out for 10 minutes. Thereaction mixture was then added to 1200 ml of water and extractedseveral times with methylene chloride. The combined organic phases werewashed with cold-saturated sodium hydrogen carbonate solution. Afterdrying over sodium sulfate, the solvent was distilled off using a rotaryevaporator. 13.0 g (80%) of 8-hydroxy-6-oxo-octanoic acid methyl esterwere obtained.

¹³C NMR (CDCl₃): δ=23.4, 25.3, 34.0, 42.8, 45.2, 51.7, 57.9, 174.1,211.0

EXAMPLE 6

A 100 ml autoclave was charged under argon with 9.4 g (50 mmol) of7,8-epoxy-6-oxo-octanoic acid methyl ester, with 0.4 g of platinum(IV)oxide catalyst, and with 50 ml of ethyl acetate. The hydrogenation wascarried out for 16 hours at 20° C., at a constant pressure of 50 barpure H₂ and with intensive stirring. When the reaction was complete, thecatalyst was filtered off and the solvent was distilled off using arotary evaporator. Purification of the residue by column chromatography(silica gel, ethyl acetate/n-hexane) yielded 6.3 g (67%) of8-hydroxy-6-oxo-octanoic acid methyl ester.

EXAMPLE 7

39.1 g (250 mmol) of sodium percarbonate were added in four portions atroom temperature, over a period of 2 hours, with stirring, to 13.9 g (82mmol) of 6-oxo-7-octenoic acid methyl ester in 210 ml of methanol. Afterstirring for a further one hour at room temperature, the reactionmixture was added to 1000 ml of water and extracted several times withmethylene chloride. The combined organic phases were washed with water.After drying over sodium sulfate, the solvent was distilled off using arotary evaporator. 13.5 g (88%) of 7,8-epoxy-6-oxo-octanoic acid methylester were obtained.

¹³C NMR (CDCl₃): δ=21.8, 23.2, 32.4, 41.5, 50.1, 57.4, 66.5, 172.5,207.4

1. Process for the preparation of compounds of the general formula I

in which R¹ represents a C₁-C₂₀-alkyl group, a C₃-C₁₂-cycloalkyl group,a C₇-C₁₂-aralkyl group or a mono- or bi-nuclear aryl group, wherein aketone of formula II

in which R¹ is as defined above, is subjected to asymmetrichydrogenation.
 2. Process according to claim 1, wherein the asymmetrichydrogenation is carried out in the presence of a ruthenium-diphosphinecomplex of formulae VI to XII: [RuHal₂D]_(n) (L)_(x) VI [RuHalAD]⁺Y⁻ VIIRuD_(n)OOCR²OOCR³ VIII [RuH_(x)D_(n)]^(m+)Y_(m) ⁻ IX [RuHal (PR⁴₂R⁵)D]²⁺Hal₂ ⁻ X [RuHHalD₂] XI [DRu (acac)₂] XII

wherein: acac represents acetyl acetonate, D represents a diphosphine ofthe general formula XIII, Hal represents halogen, R² and R³ are the sameor different and represent alkyl having up to 9 carbon atoms, which isoptionally substituted by halogen, or represent phenyl which isoptionally substituted by alkyl having from 1 to 4 carbon atoms, orrepresent an α-aminoalkyl acid having up to 4 carbon atoms, or togetherform an alkylidene group having up to 4 carbon atoms, R⁴ and R⁵ are thesame or different and represent optionally substituted phenyl, Yrepresents Cl, Br, I, ClO₄, BE₄ or PF₆, A represents an unsubstituted orsubstituted benzene ring, L represents a neutral ligand n and m eachrepresent 1 or 2, x represents 0 or 1, wherein in formula IX nrepresents 1 and m represents 2 when x=0, and n represents 2 and mrepresents 1 when x=1 and as the optically active diphosphine ligands Dare compounds of the general formula XIII

wherein: Q represents a group bridging the two P atoms and having from 2to 24 carbon atoms and optionally from 1 to 4 hetero atoms, the bridgingbeing formed by at least 2 of the carbon atoms and optionally from 1 to4 of the hetero atoms, R⁶-R⁹ are the same or different and representalkyl groups having from 1 to 18 carbon atoms, cycloalkyl groups havingfrom 5 to 7 carbon atoms or aryl groups having from 6 to 12 carbonatoms.
 3. Process according to claim 1, wherein the asymmetrichydrogenation is carried out at temperatures of from approximately 10°C. to approximately 140° C. and under a pressure of approximately from 1to 100 bar.
 4. Process according to claim 1, wherein the asymmetrichydrogenation is carried out with reaction times of from 2 to 48 hourswith a molar ratio between ruthenium in complexes VI to XII and thecompounds II to be hydrogenated are approximately 0.001 to approximately5 mol %.
 5. 8-Hydroxy-6-oxo-octanoic acid esters of the general formulaII

in which R¹ represents a C₁-C₂₀-alkyl group, a C₃-C₁₂-cycloalkyl group,a C₇-C₁₂-aralkyl group or mono- or bi-nuclear aryl group. 6.7,8-Epoxy-6-oxo-octanoic acid esters of the general formula III

in which R¹ represents a C₁-C₂₀-alkyl group, a C₃-C₁₂-cycloalky group, aC₇-C₁₂-aralkyl group or a mono- or bi-nuclear aryl group.
 7. Process forthe preparation of (R)-(+)-α-lipoic acid of formula (R)-(+)-IV

wherein the compounds II according to claim 1 are subjected toasymmetric hydrogenation to form the compounds (S)-I, and saidcompounds, a) are converted, in organic solution, with a sulfonic acidchloride and a tertiary nitrogen base, into the bissulfonic acid esterof (S)-I, b) the compound obtained in step a) is reacted, in a polarsolvent, with sulfur and an alkali metal sulfide to form the(R)-(+)-α-lipoic acid ester, and c) that ester is, optionally, convertedinto (R)-(+)-α-lipoic acid.
 8. Process for the preparation of(S)-(−)-α-lipoic acid of formula (S)-(−)-IV

wherein the compounds II according to claim 1 are subjected toasymmetric hydrogenation to form the compounds (R)-I, and saidcompounds, a) are converted, in organic solution, with a sulfonic acidchloride and a tertiary nitrogen base, into the bissulfonic acid esterof (R)-I, b) the compound obtained in step a) is reacted, in a polarsolvent, with sulfur and an alkali metal sulfide to form the(S)-(−)-α-lipoic acid ester, and c) that ester is, optionally, convertedinto (S)-(−)-α-lipoic acid.